Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial.

BACKGROUND: Induction with ibrutinib and rituximab provides an opportunity to minimise chemotherapy exposure, because upfront use of these targeted therapies could result in remission without chemotherapy and allow for consolidation with only four cycles of chemotherapy instead of the conventional eight. We aimed to determine the activity and safety of ibrutinib-rituximab induction followed by shortened chemoimmunotherapy (four cycles) with rituximab plus hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HCVAD) alternating with methotrexate-cytarabine in previously untreated patients with mantle cell lymphoma. METHODS: We did a single-centre, single-arm, phase 2 trial in previously untreated patients with mantle cell lymphoma. Eligible patients were aged 65 years or younger and had serum bilirubin of less than 1·5 mg/dL, creatinine clearance of 30 mL/min or more, Eastern Cooperative Oncology Group performance status of 2 or less, and cardiac ejection fraction 50% or more by echocardiogram. Patients received 12 cycles of ibrutinib-rituximab induction (part A; oral ibrutinib 560 mg daily and intravenous rituximab 375 mg/m2 weekly for the first 4 weeks and then on day 1 of cycles 3-12). As soon as patients had a complete response, four cycles of R-HCVAD alternating with methotrexate-cytarabine (part B) were administered. If they did not have a complete response or had a partial response, patients received two cycles of R-HCVAD alternating with methotrexate-cytarabine followed by reassessment, up to a total of eight cycles. Patients were taken off study if they had stable disease or progression during R-HCVAD. The primary outcome was the overall response rate after part A. The analyses were conducted on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT02427620. FINDINGS: 131 patients were enrolled between June 12, 2015, and Dec 6, 2018. The median age was 56 years (IQR 49-60). 58 (50%) of 117 patients had high Ki-67 (≥30%). 129 (98%, 95% CI 95-100) of 131 patients had an overall response in part A. The most common grade 3-4 adverse events were lymphocytopenia (19 [14%] of 131), skin rash (16 [12%]), thrombocytopenia (12 [9%]), infections (11 [8%]), and fatigue (ten [8%]) in part A and lymphocytopenia (96 [73%]), leukocytopenia (42 [32%]), thrombocytopenia (40 [30%]), and neutropenia (26 [20%]) in part B. There was one on-study death, which was not deemed to be treatment-related. INTERPRETATION: Induction with ibrutinib-rituximab in the frontline treatment of young patients with mantle cell lymphoma is active and safe. This approach allowed minimisation of the number of chemotherapy cycles, thereby reducing the adverse events associated with chemotherapy. Newer trials bringing the next-generation Bruton's tyrosine kinase inhibitors into the frontline setting might obviate the need for chemotherapy altogether in patients with mantle cell lymphoma. FUNDING: Pharmacyclics, Janssen.

Secondary Philadelphia chromosome acquired during therapy of acute leukemia and myelodysplastic syndrome.

The Philadelphia chromosome resulting from t(9;22)(q34;q11.2) or its variants is a defining event in chronic myeloid leukemia. It is also observed in several types of de novo acute leukemia, commonly in B lymphoblastic leukemia, and rarely in acute myeloid leukemia, acute leukemia of ambiguous lineage, and T lymphoblastic leukemia. Acquisition of the Philadelphia chromosome during therapy of acute leukemia and myelodysplastic syndrome is rare. We reported 19 patients, including 11 men and 8 women with a median age of 53 years at initial diagnosis. The diagnoses at initial presentation were acute myeloid leukemia (n = 11), myelodysplastic syndrome (n = 5), B lymphoblastic leukemia (n = 2), and T lymphoblastic leukemia (n = 1); no cases carried the Philadelphia chromosome. The Philadelphia chromosome was detected subsequently at relapse, or at refractory stage of acute leukemia or myelodysplastic syndrome. Of 14 patients evaluated for the BCR-ABL1 transcript subtype, 12 had the e1a2 transcript. In 11 of 14 patients, the diseases before and after emergence of the Philadelphia chromosome were clonally related by karyotype or shared gene mutations. Of 15 patients with treatment information available, 7 received chemotherapy alone, 5 received chemotherapy plus tyrosine kinase inhibitors, 2 received tyrosine kinase inhibitors only, and 1 patient was not treated. Twelve patients had follow-up after acquisition of the Philadelphia chromosome; all had persistent/refractory acute leukemia. Thirteen of 15 patients died a median of 3 months after the emergence of the Philadelphia chromosome. In summary, secondary Philadelphia chromosome acquired during therapy is rare, and is associated with the e1a2 transcript subtype, terminal disease stage, and poor outcome.

Solitary plasmacytomas: outcome and prognostic factors after definitive radiation therapy.

BACKGROUND: The objective of this study was to review the outcome of patients with solitary plasmacytoma (SP) after definitive radiation therapy. METHODS: The authors retrospectively reviewed 84 patients with SP who were diagnosed and treated at The University of Texas MD Anderson Cancer Center during 1988 to 2008. The impact of tumor anatomic site, tumor size, and the presence of serum and urinary paraprotein at diagnosis was assessed on local control, survival, and the risk of developing multiple myeloma (MM). RESULTS: Fifty-nine patients (70%) had bone SP, and 25 patients (30%) had extramedullary SP. Serum paraprotein was present in 39 patients (46%). The median radiation dose was 45 grays (Gy) (range, 36-53.4 Gy). Local control was achieved in 77 patients (92%). Neither radiation dose nor tumor size predicted local control. The 5-year rate of progression to MM was 47% and was higher for patients with bone SP (56% vs 30% for extramedullary SP; P = .021), and patients who had serum paraprotein detected at diagnosis (60% vs 39%; P = .016). On univariate analysis, patients aged <60 years and men had higher rates of progression to MM, although the differences were not significant (P = .048 and P = .29, respectively). Multivariate analysis revealed that bone location and serum protein at diagnosis were associated statistically with progression to MM. The 5-year overall survival rate for the entire patient cohort was 78%, and no difference was observed between patients who had bone SP versus extramedullary SP (76% vs 85%, respectively; P = .274). CONCLUSIONS: The current results indicated that definitive radiation therapy for SP can provide excellent local control. Progression to MM remains the main problem and is more common among patients with bone SP and those who have serum paraprotein detected at diagnosis.

Incidence of gastric involvement in patients with nongastrointestinal extranodal marginal zone lymphoma.

BACKGROUND: The current study was conducted to determine the incidence of gastric involvement in patients presenting with extranodal marginal zone lymphoma (MZL) outside the gastrointestinal (GI) tract and to identify clinical or laboratory parameters that predict gastric involvement in such cases. METHODS: The records of 121 consecutive patients who presented with non-GI extranodal MZL and had undergone esophagogastroduodenoscopy (EGD) as part of their initial workup were retrospectively reviewed. The authors assessed the presence of occult gastric MZL in these patients and possible associations with demographic characteristics; anatomic site of initial presentation; Helicobacter pylori (H. pylori) infection; Zubrod score; International Prognostic Index (IPI); B symptoms; and serum lactate dehydrogenase, hemoglobin, albumin, and ß2-microglobulin levels. RESULTS: The median age at diagnosis of non-GI MZL was 59 years. The most common primary tumor sites were the salivary/parotid gland (32 patients), ocular adnexa (26 patients), skin (19 patients), and lung (17 patients). Twenty-two patients (18%) were found to have gastric involvement on EGD. Using logistic regression analysis, factors found to be associated with gastric involvement included: high IPI score (odds ratio [OR], 3.70; P = .03), female sex (OR, 6.50; P = .02), serum ß2-microglobulin level of ≥ 2.5 mg/L (OR, 3.69; P = .02), and involvement of the aerodigestive mucosal/glandular tissue (OR, 4.50; P = .004). On multivariate logistic analysis, aerodigestive mucosal/glandular sites, H. pylori infection, and an elevated ß2-microglobulin level were found to be associated with gastric involvement. CONCLUSIONS: Routine EGD is recommended for patients with non-GI MZL, particularly those with primary aerodigestive mucosal/glandular tissue involvement or those with a high IPI, female sex, elevated serum ß2-microglobulin level, or H. pylori infection regardless of the primary tumor site.

The utility of flow cytometric immunophenotyping in cytopenic patients with a non-diagnostic bone marrow: a prospective study.

Cytopenia is a common problem in hematology outpatient clinics and among hospitalized patients. A bone marrow (BM) aspirate and biopsy are often performed to rule out an infiltrative versus intrinsic BM process, such as myelodysplastic syndrome (MDS). We have previously described a flow cytometric (FCM) assay useful in diagnosing MDS and demonstrated its good correlation with "gold standard" morphologic and cytogenetic criteria. In this study, we prospectively tested the utility of the FCM assay in 102 cytopenic patients with BMs showing neither diagnostic morphological dysplasia nor abnormal cytogenetics. FCM, following our published criteria, was positive in 22 cases (21.6%), intermediate in 11 cases (10.8%) and negative in 69 cases (67.6%). With a median follow-up period of 11 months (range, 4-24 months), 12 (11.8%) patients were proven to have or/develop MDS or related BM diseases (group-1); 61 (59.8%) patients had their cytopenia(s) attributed to various medical causes (group-2). In the remaining 29 patients, the causes of cytopenia(s) were not found, and some had the features consistent with the recently defined clinical entity -- idiopathic cytopenia of uncertain significance. A positive FCM result was significantly more prevalent (9/12, 75%) in group-1 patients; while a negative FCM result was significantly more frequent in group-2 patients (4/61, 7%) (p<0.0001) with a positive predictive value of 69% and a negative predictive value of 95%. We conclude that FCM analysis of myelomonocytic maturation has diagnostic utility in cytopenic patients who have an inconclusive BM examination by morphologic and cytogenetic evaluation, and may therefore be a useful adjunct in clinical management of these patients.